Many actions of adenosine are those of a rescue autacoid whose main function is to protect tissues from ischemia. To study these processes in humans we propose to evoke local adenosine mechanisms in the forearm skeletal muscle by increased metabolic demands during restriction of blood flow (sustained isometric exercise). Ischemic exercise, but not ischemia alone, induces systemic sympathetic activation (the "exercise pressor reflex") due in part to release of metabolites that activate muscle afferents. We hypothesize that adenosine is a metabolic trigger of this reflex. In agreement with this hypothesis, injection of adenosine into the brachial artery triggers sympathetic stimulation that mimics muscle afferent activation. This effect is localized to the forearm and is not explained by pain or local vasodilation. Conversely, the blockade of forearm adenosine receptors with intrabrachial theophylline blunts the exercise pressor reflex Finally, we have recently found that interstitial levels of adenosine are increased during ischemic exercise of the forearm, but not during ischemia alone, which agrees with the observation that ischemia alone is not a sufficient stimulus to trigger muscle afferent activation. We propose to further test this hypothesis by modulating interstitial adenosine levels with graded ischemic exercise, and by potentiating or blocking endogenous adenosine mechanisms. Adenosine-induced sympathetic activation seems at odds with its postulated role as a protective autacoid against ischemia. It is possible, however, that local adenosine exerts a compensatory inhibition of norepinephrine release, with the potential of restraining sympathetically-mediated vasoconstriction. We propose to test the hypothesis that, under physiological conditions, local adenosine inhibits the release of norepinephrine evoked by local ischemia or by reflex sympathetic activation.